TY - JOUR
T1 - Brain-specific tryptophan hydroxylase 2 (TPH2)
T2 - A functional Pro206Ser substitution and variation in the 5′-region are associated with bipolar affective disorder
AU - Cichon, Sven
AU - Winge, Ingeborg
AU - Mattheisen, Manuel
AU - Georgi, Alexander
AU - Karpushova, Anna
AU - Freudenberg, Jan
AU - Freudenberg-Hua, Yun
AU - Babadjanova, Gulia
AU - Van den Bogaert, Ann
AU - Abramova, Lilia I.
AU - Kapiletti, Sofia
AU - Knappskog, Per M.
AU - Mckinney, Jeffrey
AU - Maier, Wolfgang
AU - Abou Jamra, Rami
AU - Schulze, Thomas G.
AU - Schumacher, Johannes
AU - Propping, Peter
AU - Rietschel, Marcella
AU - Haavik, Jan
AU - Nöthen, Markus M.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] controls a broad range of biological functions that are disturbed in affective disorder. In the brain, 5-HT production is controlled by tryptophan hydroxylase 2 (TPH2). In order to assess the possible contribution of TPH2 genetic variability to the aetiology of bipolar affective disorder (BPAD), we systematically investigated common and rare genetic variation in the TPH2 gene through a sequential sequencing and SNP-based genotyping approach. Our study sample comprised two cohorts of BPAD from Germany and Russia, totalling 883 patients and 1300 controls. SNPs located in a haplotype block covering the 5′ region of the gene as well as a rare, non-synonymous SNP, resulting in a Pro206Ser substitution, showed significant association with bipolar disorder. The odds ratio for the minor allele in the pooled sample was 1.5 (95% CI 1.2-1.9) for rs11178997 (in the 5′-associated haplotype block) and 4.8 (95% CI 1.6-14.8) for rs17110563 encoding the Pro206Ser substitution. Examination of the functional effects of TPH2 Pro206Ser provided evidence for a reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism in BPAD.
AB - The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] controls a broad range of biological functions that are disturbed in affective disorder. In the brain, 5-HT production is controlled by tryptophan hydroxylase 2 (TPH2). In order to assess the possible contribution of TPH2 genetic variability to the aetiology of bipolar affective disorder (BPAD), we systematically investigated common and rare genetic variation in the TPH2 gene through a sequential sequencing and SNP-based genotyping approach. Our study sample comprised two cohorts of BPAD from Germany and Russia, totalling 883 patients and 1300 controls. SNPs located in a haplotype block covering the 5′ region of the gene as well as a rare, non-synonymous SNP, resulting in a Pro206Ser substitution, showed significant association with bipolar disorder. The odds ratio for the minor allele in the pooled sample was 1.5 (95% CI 1.2-1.9) for rs11178997 (in the 5′-associated haplotype block) and 4.8 (95% CI 1.6-14.8) for rs17110563 encoding the Pro206Ser substitution. Examination of the functional effects of TPH2 Pro206Ser provided evidence for a reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism in BPAD.
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U2 - 10.1093/hmg/ddm286
DO - 10.1093/hmg/ddm286
M3 - Article
C2 - 17905754
AN - SCOPUS:37549044251
SN - 0964-6906
VL - 17
SP - 87
EP - 97
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 1
ER -